This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The effects of simian immunodeficiency virus (SIV) on blood-brain barrier permeability are likely initiated by glial response to the presence of virus in the central nervous system. This localized inflammatory reaction to the virus drives dysregulation of the endothelium by RNA modulation and protein phosphorylation. We determined a novel downregulation of CD263, a TNF decoy receptor in SIV stimulated endothelial cells, that normally serves to mitigate the damaging effects of TRAIL when the endothelium encounters proinflammatory stimuli. Supernatant from SIVmac251 infected macrophage was sufficient to cause astrocytes to overproduce TNF-[unreadable] by about 4-fold. Further, the same supernatant increased CCL2 and CXCL8 production in endothelial cells. The activation of the TNF-[unreadable] receptor in endothelial cells by its ligand causes activation of NF[unreadable]B in the endothelium. This leads to the subsequent upregulation/phosphorylation of MLCK, actin cytoskeletal reorganization, and redistribution of ZO-1.